Zurich Open Repository andArchiveUniversity of ZurichMain LibraryStrickhofstrasse 39CH-8057 Zurichwww.zora.uzh.ch

Year: 2017

Randomized clinical study assessing two membranes for guided boneregeneration of peri-implant bone defects: clinical and histological outcomes

at 6 months

Naenni, Nadja ; Schneider, David ; Jung, Ronald E ; Hüsler, Jürg ; Hämmerle, Christoph H F ; Thoma,Daniel S

Abstract: PURPOSE To test whether or not one of two membranes is superior for peri-implant-guidedbone regeneration in terms of clinical and histologic outcomes. MATERIAL AND METHODS In 27patients, 27 two-piece dental implants were placed in single-tooth gaps in the esthetic area. Buccaldehiscence and/or fenestration-type defects were regenerated using demineralized bovine bone mineraland randomly covered with either a resorbable membrane (RES) or a titanium-reinforced non-resorbablemembrane (N-RES). Clinical measurements included vertical defect resolution and the horizontal thick-ness of regenerated bone at implant placement and at 6 months. Statistics were performed by means ofnonparametric testing. RESULTS The remaining mean vertical defect measured 4 mm (±2.07) (RES)and 2.36 mm (±2.09) (N-RES) (P = 0.044) at baseline and 0.77 mm (±0.85) (RES) and 0.21 mm (±0.80)(N-RES) (P = 0.021) at re-entry. This translated into a defect resolution of 85% (RES) and 90.7% (N-RES) (P = 0.10). The horizontal thickness after augmentation measured 3.46 mm (±0.52) (RES) and2.82 mm (±0.50) (N-RES) (P = 0.004). The mean loss in horizontal thickness from baseline to re-entrymeasured 2.23 mm (SD ±1.21) (RES) and 0.14 mm (±0.79) (N-RES) (P = 0.017). The horizontalchanges in thickness at the implant shoulder level were statistically significant between the groups (P= 0.0001). CONCLUSIONS Both treatment modalities were clinically effective in regenerating bone asdemonstrated by a similar horizontal thickness and vertical defect fill at 6 months. The N-RES groupexhibited significantly less horizontal bone thickness reduction from baseline to follow-up.

DOI: https://doi.org/10.1111/clr.12977

Posted at the Zurich Open Repository and Archive, University of ZurichZORA URL: https://doi.org/10.5167/uzh-126657Journal ArticleUpdated Version

Originally published at:Naenni, Nadja; Schneider, David; Jung, Ronald E; Hüsler, Jürg; Hämmerle, Christoph H F; Thoma,Daniel S (2017). Randomized clinical study assessing two membranes for guided bone regenerationof peri-implant bone defects: clinical and histological outcomes at 6 months. Clinical Oral ImplantsResearch, 28(10):1309-1317.DOI: https://doi.org/10.1111/clr.12977

Randomized clinical study assessing two membranes for guided

bone regeneration of peri-implant bone defects: clinical and histological

outcomes at 6 months

Nadja Naenni1, David Schneider1, Ronald E. Jung1, Jürg Hüsler, Christoph H.F.

Hämmerle1, Daniel S. Thoma1

Key words: dental implants, bone and bones, bone regeneration, membranes,

alveorlar ridge augmentation (all Mesh terms)

Running title: guided bone regeneration using two different membranes

Address for correspondence:

PD Dr. Daniel S. Thoma Clinic of Fixed and Removable Prosthodontics and Dental Material Science Center of Dental Medicine, University of Zurich Plattenstrasse 11 CH-8032 Zurich, Switzerland Phone: +41 44 634 32 60 Fax: +41 44 634 43 05 e-mail: daniel.thoma@zzm.uzh.ch

1 Clinic for Fixed and Removable Prosthodontics and Dental Material Science,

Center of Dental Medicine, University of Zurich, Zurich, Switzerland

Abstract

Purpose: To test whether or not one out of two membranes is superior for peri-

implant guided bone regeneration in terms of clinical and histologic outcomes.

Materials and Methods: In 27 patients, 27 two-piece dental implants were

placed in single-tooth gaps in the esthetic area. Buccal dehiscence and/or

fenestration-type defects were regenerated using demineralized bovine bone

mineral (DBBM) and randomly covered with either a resorbable membrane (RES)

or a titanium-reinforced non-resorbable membrane (N-RES). Clinical

measurements included vertical defect resolution and the horizontal thickness of

regenerated bone at implant placement and at 6 months. Statistics were

performed by means of non-parametric testing.

Results: The remaining mean vertical defect measured 4.00mm (±2.07) (RES)

and 2.36mm (±2.09) (N-RES) (p=0.044) at baseline and 0.77mm (±0.85) (RES)

and 0.21mm (±0.80) (N-RES) (p=0.021) at re-entry. This translated into a

defect resolution of 85% (RES) and 90.7% (N-RES) (p=0.10). The horizontal

thickness after augmentation measured 3.46mm (±0.52) (RES) and 2.82mm

(±0.50) (N-RES) (p=0.004). The mean loss in horizontal thickness from baseline

to re-entry measured 2.23mm (SD±1.21) (RES) and 0.14mm (±0.79) (N-RES)

(p=0.017). The horizontal changes in thickness at the implant shoulder level

were statistically significant between the groups (p=0.0001).

Conclusions: Both treatment modalities were clinically effective in regenerating

bone as demonstrated by a similar horizontal thickness and vertical defect fill at 6

months. The N-RES group exhibited significantly less horizontal bone thickness

reduction from baseline to follow-up.

Introduction

Guided bone regeneration (GBR) procedures are routinely performed in dental

practice to regenerate missing hard tissue volume prior to or simultaneously with

dental implant placement (Hammerle et al., 2002, Bornstein et al., 2008,

Hammerle and Karring, 1998). Various GBR techniques have been proposed and

numerous materials are available to the practitioner (Donos et al., 2008, Esposito

et al., 2006, Aghaloo and Moy, 2007, Jensen and Terheyden, 2009, Benic and

Hammerle, 2014).

Initially, the GBR technique was developed to regenerate periodontal tissues

(Nyman et al., 1982, Gottlow et al., 1984, Gottlow et al., 1986). Later, this

technique was also suggested and applied for bone augmentation around dental

implants (Jovanovic et al., 1992, Karring et al., 1993). For that purpose

autogenous bone or bone substitute materials in combination with non-resorbable

barrier membranes were used. The integration of titanium reinforcements into

non-resorbable expanded polytetrafluorethylene (ePTFE) membranes increased

their stability and allowed the membrane to be formed into an adequate shape.

Despite high clinical success rates (Friedmann et al., 2001, von Arx et al., 2001,

Buser et al., 2002), ePTFE membranes exhibit two main clinical disadvantages: i)

an additional surgery procedure is necessary to remove the membrane; ii)

increased rates of membrane exposure leading to impaired wound healing,

especially during the early healing phase (Piette et al., 1995, Moses et al., 2005)

and, bacterial colonization with subsequent infection of the augmented site

(Becker et al., 1994, Simion et al., 1994, Strietzel, 2001).

In order to overcome these shortcomings, resorbable membranes were

introduced. Among these, collagen membranes are well documented and render

high clinical success rates (Pitaru et al., 1987, Zitzmann et al., 1997, Hockers et

al., 1999, Zitzmann et al., 2001a, Friedmann et al., 2001, Hammerle and Lang,

2001, Hammerle et al., 1998). However, these relatively soft membranes do not

maintain space per se and a compression of the regenerated site can potentially

result in a displacement of the augmentation material (Strietzel et al., 2006,

Friedmann et al., 2002)

To date, there is weak evidence with respect to the morphological changes of the

augmented tissues following GBR procedures around dental implants. A variety of

studies focused on the stability of the mucosal margin (Jemt et al., 2006, Priest,

2003, Grunder, 2000) and the height of the papilla around implant-supported

crowns (Cardaropoli et al., 2006, Chang et al., 1999). However, the changes of

contour and morphology of the labial peri-implant tissues have not been

investigated in detail (Jemt et al., 2006, Jemt and Lekholm, 2003) until recently

(Jensen et al., 2014, Schneider et al., 2014).

The aim of the present study was to test whether or not one of two GBR

membranes is superior to the other in terms of: i) vertical defect resolution and

bucco-oral width of regenerated bone at the implant shoulder at 6 months ii)

postoperative complications during the 6-month follow-up and, iii) histologically

assessed mineralized tissue at 6 months.

Materials and methods

This study was designed as a prospective randomized controlled clinical trial. All

procedures and materials were approved by the local ethical committee (Nr.

2010-0051/5). Twenty-seven patients with a single tooth gap (central incisor to

premolar in the maxilla or mandible) in need of implant treatment were

consecutively recruited at the Clinic of Fixed and Removable Prosthodontics and

Dental Material Science, Center of Dental Medicine, the University of Zurich,

Switzerland. Informed consent was obtained from all patients prior to the start of

the study. The following inclusion criteria were applied:

1. Periodontally healthy patients (periodontal probing depths <4mm)

2. Good oral hygiene (full mouth plaque index <25%) (O'Leary et al., 1972)

3. Adequate control of inflammation (full mouth bleeding on probing <25%

(Ainamo and Bay, 1975)

4. Single tooth gaps with a buccal alveolar bone deficiency

5. Planned implant placement >6 weeks after tooth extraction

6. A dehiscence or fenestration-type defect after implant placement

Patients not meeting all inclusion criteria were not enrolled prior to surgery (1-5)

or excluded from the study after implant placement (6).

Enrolled patients were scheduled for a baseline visit. This examination

encompassed the following assessments: clinical periodontal parameters

(periodontal probing depth (PPD), plaque control record (PCR), bleeding on

probing (BOP), all at six sites around the adjacent teeth; the width of keratinized

tissue (KM) on the buccal side of the two neighboring teeth, a conventional

impression (President, Coltène/Whaledent, Altstätten, Switzerland) and clinical

photographs of the planned implant site. Two to 4 weeks after the baseline visit,

implant surgery was performed.

Surgical protocol

Prior to the start of the surgery, patients had to rinse with a 0.2% Chlorhexidine

solution for one minute and were given antibiotics (Amoxicillin 750mg, Sandoz

Pharmaceuticals, Risch, Switzerland) and analgesics (Mefenacid 500mg, Mepha

Pharma AG, Basel, Switzerland). Local anesthesia was achieved with Articaine

hydrochloride (Rudocaine forte®, Streuli, Switzerland). Following an intrasulcular

incision around the two neighbouring teeth and a vertical releasing incision at the

disto-buccal aspect of the distal neighboring tooth a mucoperiosteal flap was

raised. The implant site was prepared according to the manufacturers

recommendations and a screw type, rough surface two-piece dental implant

(OsseoSpeed, ASTRA TECH Implant System, DENTSPLY Implants, Mölndal,

Sweden) was placed in a prosthetically ideal position using a surgical stent.

Implants had to reach primary stability. Subsequently, the peri-implant osseous

defect was measured using a calibrated periodontal probe (PCP-11, Hu-Friedy,

Chicago, USA). Clinical measurements included defect height, depth, width and

infrabony defect size (Fig.1). If no bone defect was present and no bone

augmentation was needed, the patient was excluded from the study.

Simultaneous GBR was performed using demineralized bovine bone mineral

(DBBM, BioOss spongiosa granules, particle size 0.25-1.0mm; Geistlich Pharma

AG, Wolhusen, Switzerland). At this time-point according to a computer-

generated randomization list and using sealed envelopes (prepared by the study

monitor), either one of two membranes was applied:

i) resorbable collagen membrane (BioGide, Geistlich Pharma AG,

Wolhusen, Switzerland) (RES)

ii) non-resorbable ePTFE-membrane (Gore-Tex®, W.L. Gore & Assoc.,

Flagstaff, Arizona, USA) (N-RES)

The peri-implant defect and the missing hard tissue contour were built up with

DBBM particles. The horizontally augmented thickness on the buccal side was

measured at the level of the implant shoulder (Fig.1). In group RES, the

resorbable membrane was cut to fit the osseous defect covering the respective

bone regenerate. Two to three resorbable pins made of polylactic acid (Inion

Pins; Geistlich AG, Wolhusen, Switzerland) were then used to tack the

membrane buccally onto the underlying bone to avoid membrane and DBBM

displacement. In group N-RES, the ePTFE-membrane was extraorally shaped and

adapted to fit the defect size. Non-resorbable titanium pins (Frios®, Friadent

GmbH, Mannheim, Germany) were used to stabilize the membrane. Both

membranes had to overlap the borders of the augmented site defect by at least

2mm. On the palatal/lingual aspect the membranes were placed under the flap.

Subsequently, releasing incisions within the periosteum were performed on the

buccal aspect of the flap to allow for a tension-free wound closure. Primary

wound closure was obtained using non-resorbable sutures (Gore-Tex suture;

Gore, Flagstaff, AZ, USA).

The patients were then instructed to refrain from mechanical plaque removal in

the surgical area for 7-10 days and had to follow a strict postoperative regimen.

This consisted of rinsing with an aqueous solution of 0.2% chlorhexidine

(Kantonsapotheke, Zurich, Switzerland), of a medication with antibiotics for 5

days (Amoxicillin 750mg, Sandoz Pharmaceuticals, Risch, Switzerland) and

analgesics (Mefenacid 500mg, Mepha Pharma AG, Basel, Switzerland) according

to individual needs.

Follow-up visits

Suture removal was performed 7-10 days after implant placement. Patients were

then recalled at 4 weeks, at 3 and at 6 months to assess the soft tissue condition

(normal, swollen, red, dehiscence). In addition, a conventional impression

(President, Coltène/Whaledent, Altsätten, Switzerland) and clinical photographs

of the implant sites were taken at each time-point. At 6 months, re-entry surgery

was performed in all patients by elevating a full thickness flap to again measure

the vertical defect fill and the horizontal thickness of the bone at the buccal

aspect of the implant with a calibrated periodontal probe (PCP-11, Hu-Friedy,

Chicago, USA). These measurements were performed at the level of the implant

shoulder. In addition, core-biopsies were harvested using a trephine bur with an

inner diameter of 1.8mm. The biopsies were performed at a level of 3mm below

the implant shoulder perpendicular to the long axis of the implant with a sink

depth of 3mm (Figure 3). The cover screw was removed and replaced by a

healing abutment. The mucoperiosteal flap was adjusted and sutured to fit

around the neck of the healing abutment. If a buccal concavity was persisting at

this time-point, a soft tissue grafting procedure (Seibert, 1983, Schneider et al.,

2011, Thoma et al., 2016) was performed and implants left submerged for

another 2 months before performing abutment connection.

Histologic preparation and analyses

The biopsies were fixed in 4% buffered formalin for at least 48 hours. The

specimens were then rinsed in running tap water and demineralized for 72 hours

(USEDECALC BioSystems, Muttenz, Switzerland). After decalcification they were

watered again for 1 hour and dehydrated in a graded series of increasing ethanol

concentrations and thereafter infiltrated with xylol and paraffin in a vacuum

infiltration tissue processor (Tissue-Tek VIP, Sakura-Finetek, Torrance, CA/USA).

Specimens were then embedded in paraffin and cut into 2-5µm thickness using a

paraffin-microtome (MICROM, Medite GmbH, Dietlikon, Switzerland). The

specimens were dried with warm air (Wärmeschrank, Bittmann, Basel,

Switzerland), de-paraffinized with xylol and stained with Haemalaun-Eosin

(Robert Hooke 1665, Böhmer 1865).

A qualitative analysis was performed with a light-microscope (Leica CTR6000,

Leica, Wetzlar, Germany) at a magnification of x200. Pictures of each specimen

were taken with a camera attached to the microscope (Leica DFC450, Leica,

Wetzlar, Germany) for further analysis. All available sections were quantitatively

assessed for different tissue components by applying standard histological

morphometrical techniques (Weibel 1980; Gundersen et al. 1988). The different

components (background, non-mineralized tissue, mineralized tissue and bone

substitute material) and their respective amount calculated in % within a central

region of interest. Measurements were carried out using an image analysis

software (LAS V4.3, Leica, Wetzlar, Germany).

Statistical evaluation and analysis

Outcome measures

The following primary and secondary outcome variables were analyzed:

Primary: vertical defect fill (dehiscence defect at the buccal aspect of the

implant)

Secondary: horizontal thickness of the regenerated bone at the buccal aspect of

the implant; defect depth, defect width and infrabony defect height; soft tissue

condition (dehiscences); clinical parameters (PPD, PCR, BOP,KM),

histomorphometric outcome measures (percentage of newly formed bone,

remaining amount of bone substitute material, bone substitute to bone contact)

Sample size calculation

The sample size was calculated according to a previously performed study using

similar primary and secondary endpoints (Jung et al., 2009). As the primary

endpoint of this study was the vertical defect fill, it was planned to recruit a total

number of 34 patients (17 per group). This would enable to detect a difference of

1mm between the test and control group with a standard deviation of σ=1 and a

significance level of α=0.05 with a power of 80%.

Descriptive statistics were applied to the data. Statistical analysis of the most

important questions was based on non-parametric tests because of small sample

sizes. Significance were determined using the Wilcoxon Mann-Whitney U-test with

SAS 9.4. The level of significance was set at P<0.0083 since 6 tests (hypotheses)

were applied for the 6 primary questions (by Bonferroni correction). A p-value

between 0.05 and 0.0083 may be considered as a borderline significance pointing

on a possible difference. Mean and standard deviations are given in the following

section. In the tables medians are reported which are analyzed by the

nonparametric tests. For analysis of possible confounders a robust mixed model

approach (with the R Package pbkrtest) was applied to a part of the data. All the

other tests were used as explorative investigations.

Results

Demographics

Eligible patients were enrolled between March 2010 and January 2013. 55

patients were initially screened. Finally, a total of 27 patients could be

randomized for treatment and included in the study (14 female, 13 male). All

patients were in good general health and had previously undergone

comprehensive dental care. They were all followed up to 6 months after implant

placement. Thirteen patients were randomized for group RES and 14 patients for

group N-RES. Seven implants were placed in the mandible, whereas 21 implants

were placed in the maxilla. The exact distribution of implant sites and locations is

depicted in Table 1.

The mean age was 51.85 years (standard deviation ±29.7). Six patients were

light smokers (≤ 10cig/day) and three patients had a history of periodontitis.

Defect dimensions at implant placement and at re-entry

All data for defect width, defect depth and infrabony defect size are displayed in

Table 2a. Results for defect width and depth were statistically significant or

borderline for the time-point (p=0.0001/p=0.003) but did not show effect of

group interaction in the more complex mixed model.

The mean vertical defect height after implant placement measured 4.00mm

(±2.07) in group RES and 2.36mm (± 2.09) in group N-RES. At 6 months, the

mean remaining vertical defect height measured 0.77mm (± 0.85) (RES) and

0.21mm (±0.80) (N-RES). Table 2b&c

Differences between the two groups were statistically borderline significant at

both time-points (p=0.044/p=0.021). Mean changes in vertical defect height

from baseline to 6 months measured 3.41mm (±2.33) (RES) and 2.14mm

(±2.06) (N-RES) (p=0.1069). Table 2b&c

This amounted to a vertical defect resolution of 85% (RES) and 90.7% (N-RES).

Seven sites (6 RES / 1 N-RES) demonstrated incomplete vertical regeneration,

whilst one site in group RES even showed an increased vertical defect height at

re-entry compared to baseline (after implant placement).

The mean horizontal thickness at the level of the implant shoulder measured

3.46mm (± 0.52) (RES) and 2.82mm (± 0.50) (N-RES) following grafting with

DBBM (p=0.0040). At 6 months, the mean horizontal thickness was 1.32mm (±

1.38) (RES) and 2.68mm (± 1.05) (N-RES) (p=0.0167). Both groups showed a

loss of horizontal thickness over time with a mean of 2.23mm (±1.21) (RES)

and 0.14mm (±0.79) (N-RES). The differences between the groups were

statistically significant (p=0.0001) See Table 2b&c.

Soft tissue condition

Although primary wound closure was obtained in all patients, a total of six

dehiscences (local adverse event) were observed during the 6-month follow-up.

Four dehiscences were observed in group RES (30%) and two in group N-RES

(14%). Five dehiscences were present at the time of suture removal. Four of

these occurred in the RES group and healed spontaneously until the 4-week

follow-up. One dehiscence in the N-RES group healed between the 4-week and 3-

month follow-up. The second dehiscence in the N-RES group occurred between

suture removal and the 4-week follow-up. This patient was advised to apply local

disinfecting agents (Plak Out Gel, Kerr Hawe SA, Bioggio, Switzerland and

Solcoseryl, Meda Pharma GmbH, Wangen-Brüttisellen, Switzerland) and was

recalled once a week for four weeks and later on once a month. The dehiscence

persisted until the re-entry surgery at 6 months.

The number of dehiscences at the different time-points is displayed in Table 3a.

The soft tissue condition at re-entry is displayed in Table 3b. Overall, in all but

one patient, the soft tissues were rated “normal” at 3 and 6 months after implant

surgery.

Clinical parameters

Probing Pocket Depth (PPD)

Mean PPD values varied between 2.27mm (±0.45mm;mesially) and 2.38mm

(±0.44mm;distally) in group RES and 2.34mm (±0.29mm;mes) and 2.50mm

(±0.42mm;dis) in group N-RES. At 6 months PPD values measured 2.24mm

(±0.32mm;mes) and 2.44mm (±0.47mm;dis) for the RES group and 2.36mm

(±0.25mm;mes) and 2.42mm (±0.35mm;dis). Results were statistically not

significant for neither mesial/distal aspect, nor between the groups and at the

two time points (p>0.05).

Plaque control record (PCR)

Plaque indices at time-point before implant placement and at 6 months did not

show to be statistically significant when compared over time. No statistically

significant differences were measured between the two groups.

Bleeding-on-probing (BOP)

BOP values did not show to be statistically significant over time for mesial values,

but decreased over time for the distal values. These were statistically borderline

significant (p=0.04).

Keratinized Tissue (KM)

The width of keratinized tissue decreased between screening (prior to surgery)

and 6 months from 4.1mm (SD 0.77;mesial) and 4.0mm (±0.43; distal) to

3.4mm (±0.47;mesial) and 2.9mm (±0.26;distal) in group RES . The

corresponding values for group N-RES were 4.3mm (±.04;mesial) and 4.2mm

(±0.2;distal) pre-surgically and decreased to 3.8mm (±0.3;mesial) and 3.6mm

(±0.3;distal) at 6 months. For both groups the differences over time were

borderline statistically significant (P=0.03).

Histologic assessment

In general, the histologic samples revealed loose DBBM particles surrounded to a

large extent by newly formed bone and embedded in a loose connective tissue.

Remodeling of the DBBM particles had taken place and led to the formation of

vacuoles with intimate bone formation along the bone substitute surface. (Fig.4)

The density of the DBBM particles and the newly formed bone as well as the

density of the connective tissue demonstrated great variation within the groups.

The histomorphometric analysis showed a mean amount of newly formed bone of

38.0% (±18.4%) (RES) and of 35.7% (±29.5%) (N-RES). The remaining amount

of DBBM was 36.4% (±8.3%) (RES) and 45.2% (±11.9%) (N-RES) revealing a

slightly better containment of the augmented bone substitute material in group

N-RES. The overall mean amount of mineralized tissue was 73.0% (±19.9%)

(RES) and 69.6% (±16.7%) (N-RES). The surface fraction of bone substitute to

bone contact measured calculated bone to bone substitute contact was 46.4%

(±25.3%) (RES) and 41.1% (±19.1%) (N-RES). The differences between the two

groups were not statistically significantly different for any of the histological

assessments (p>0.05).

Discussion

The results of the present RCT demonstrated that i) both GBR membranes were

successful in regenerating bone on the buccal side of dental implants regarding

vertical defect fill and increase in horizontal thickness; ii) the horizontal thickness

decreased to a significantly greater amount over time in group RES compared to

group N-RES; iii) wound dehiscences occurred at a rate of 30% (RES) and 14%

(N-RES), but healed with one exception during 6 months and without the need for

premature removal of the membrane; iv) the augmented DBBM underwent

remodeling processes and promoted new bone formation.

Augmentation of hard tissue simultaneous with implant placement is considered a

routine procedure with successful short- and long-term results (Chiapasco and

Zaniboni, 2009, Jung et al., 2013, Hammerle et al., 2002). This is demonstrated

by survival rates of implants placed in regenerated bone being similar when

compared to implants placed conventionally into sites without the need for bone

augmentation (Hammerle et al., 2002, Donos et al., 2008). Differences between

resorbable and non-resorbable membranes mainly exist in terms of a need for a

second stage surgery (removal of a non-resorbable membrane), a reported

higher rate of dehiscences (non-resorbable membranes) and a higher risk of a

membrane collapse (resorbable membranes) (Zitzmann et al., 1997, Wiltfang et

al., 1998, Moses et al., 2005).

In the present study, peri-implant defect dimensions were re-assessed 6 months

after GBR procedure. Defect height, width and depth were all significantly lower

at the re-entry time-point compared to the day of implant placement with

simultaneous GBR. This demonstrated a successful bone augmentation in both

groups with mean changes over time (defect resolution) ranging between

3.41mm (RES) and 2.14mm (N-RES) and a very minimal persisting defect height

remaining at reentry (0.77mm (RES) and 0.21mm (N-RES)). The difference in

decrease was statistically significant between the groups. This is supported by a

clinical multicenter study reporting a significant decrease in surface exposure

when non-resorbable membranes were used for the treatment of fenestration or

dehiscence-type defects (Dahlin et al., 1995). The remaining defect heights after

healing periods of 3-6 months measured 1.1mm (±2.3) after an initial defect

height of 4.7mm (±3.0) and were therefore slightly greater compared to the

present study. Data on resorbable collagen membranes used in studies with a

similar design reported dehiscence-type defect resolution for the combination of

DBBM plus collagen membrane of 96% (4.25mm from 4.5mm) (Jung et al. 2009)

and 91% (5.4mm from 5.8mm) (Jung et al. 2003), whereas in the present study

defect resolution amounted to 85% (RES) and 90% (N-RES) respectively. In

contrast, in a previous comparative study mean percentages of bone fill of 92%

for resorbable and 78% for non-resorbable membranes were reported favoring

the use of resorbable collagen membranes. However, in that study the relatively

high rate of membrane exposure with non-resorbable membranes often led to

premature removal due to infection. This was interpreted as the main reason for

the lower defect fill for this type of membrane. (Zitzmann et al., 1997). In the

present study, even though dehiscences occurred, no membranes were removed

prior to the 6-month re-entry time-point. In addition, dehiscences were not

associated with greater residual defect heights.

Apart from the defect resolution, which reflects how well a GBR procedure

performed in a vertical dimension, the horizontal thickness, measured at baseline

(following GBR) and at re-entry surgery, documents the stability of the

augmented area. The GBR principle is based on a membrane, which serves as a

tent to allow for bone regeneration underneath. This space-maintenance can be

obtained using a form-stable membrane or a bone substitute material that

stabilizes a non-form-stable membrane. Since in the present study the same

bone substitute material was used in both groups, the effect of the membrane in

terms of stability and containment of the augmented area could be assessed. The

horizontal thickness at baseline was greater in group RES compared to group N-

RES. At re-entry, however, the horizontal thickness in group N-RES was greater.

Whereas in both groups, a loss of horizontal thickness was observed, the loss in

group N-RES was statistically significantly smaller. This demonstrates that the

collagen membrane tended to collapse even though being supported by the bone

substitute material.

It has previously been reported that in order to avoid vertical bone loss over

time, a minimal buccal bone dimension of 2mm is required (Spray et al., 2000,

Botticelli et al., 2004). One might speculate that for a successful GBR 2mm of

buccal bone should be obtained. Keeping in mind these data and the loss of

volume that predominantly occurred with the resorbable membrane, a buccal

over contouring at the day of surgery might be recommended. The long-term fate

of augmented bone and the optimal amount of bone required for stable results

remains unknown today. More recent data even suggest that in cases with

missing buccal bone on the implant surface, the peri-implant soft tissues might

compensate and provide clinically successful outcomes (Benic et al., 2012,

Kuchler et al., 2015).

In the present study the number of wound dehiscences was comparable to results

reported in previous studies using the same membranes (Moses et al., 2005).

Though more dehiscences occurred in group RES (30%) than in group N-RES

(14%). This to some extent contradicts results from previous studies with rates

for dehiscences ranging from 11% (Dahlin et al., 1995) to 20% for non-

resorbable membranes (Chiapasco and Zaniboni, 2009) compared to rates

ranging between 5% (Chiapasco and Zaniboni, 2009) and 31% for resorbable

membranes (Jung et al., 2009). Most studies however, observed more

dehiscences with non-resorbable membranes compared to resorbable membranes

(Moses et al., 2005, Zitzmann et al., 1997). Dehiscences of non-resorbable

membranes may lead to early removal of the membrane resulting in impaired

bone regeneration. In contrast to previously published data (Moses et al., 2005)

dehiscences in the present study were not associated with obtained residual

defect heights at 6 months. In addition, the two membranes in group N-RES that

had a dehiscence, did not have to be removed prematurely. Due to the strict

application of local desinfecting agents the respective sites could be prevented

from bacterial colonization of the underlying membrane. Similarly, membranes in

group RES with dehiscences healed without the need for further surgical

intervention. One explanation that might be associated with the number of

dehiscences could be the incision design and handling of the flap.

(Dahlin et al., 1995). In the present study the incision design was standardized

and did not depend on the randomization. Incisions were made paracrestal

(palatally or lingually) in order not to compromise blood supply. Subperiosteal

incisions were made to allow for a tension-free adaptation of the wound margins.

Moreover, a factor certainly contributing to the low numbers of wound

dehiscences is a strict maintenance program. All patients in this study were

recalled regularly for a check-up at set time-points, reinstructed for oral hygiene

and supported by a professional cleaning. This was reflected in PCR values being

stable and BOP values even decreasing over time up to 6 months. Another

explantation for the higher number of dehiscences within RES group might be the

following. Being aware of having to prematurely remove non-resorbable

membranes in case of bacterial colonization, one may have tried not to

overcontour the augmentation. It could well be assumed that in order to

compensate for the horizontal resorption the surgeons augmented the sites within

RES group to a greater extent. This is maybe reflected by a higher amount in

horizontal thickness after GBR of 3.46mm (RES) versus 2.82 (N-RES).

Although clinical evidence clearly shows the successfull use of e-PTFE membranes

for bone regeneration procedures, dehiscences do occur quite often and may

compromise the surgical outcome (Zitzmann et al., 1997, Moses et al., 2005). A

possible reason for the vulnerability of these membranes towards microbial

invasion in case of early exposure might be their macroporosity allowing for

bacterial colonization of the membrane and thus leading a subsequent infection.

As an alternative to the use of e-PTFE, non-expanded, a dense

polytetrafluoroethylene (n-PTFE) was proposed due to its inherent characteristics.

Most of the available literature on the use of n-PTFE is based on pre-clinical

studies. Clinical studies are limited to case series only. Clinical procedures having

been investigated including ridge preservation techniques or the placement of

immediate implants with concomittant GBR procedures. Whether or not n-PTFE

membranes can be successfully used for GBR procedures remains to be proven.

(Carbonell et al., 2014)

Both membranes contained the augmented DBBM to a similar extent as

demonstrated by small standard deviations in both groups. In terms of bone

regeneration, great variability was observed between the different sites. The

calculated area fractions of newly formed bone range between 4% and 63%

(RES) and 11% and 98% (N-RES). This rather high heterogeneity in between the

sites is mostly due to the fact that in some biopsies, the obtained tissues

contained a very loose and only slightly mineralized structure with DBBM particles

being surrounded by a loose connective tissue. Since biopsies were taken

superficially at the buccal aspect, some of the GBR material might not have been

completely integrated and might therefore explain these differences. This is in

agreement with a previous clinical study comparing a hydrogel membrane to the

same collagen membrane used in the present study (Jung et al., 2009). In that

study, a similar re-entry surgery at 6 months was performed and revealed a

quality of newly formed bone that ranged from very dense to more soft bone.

Previous studies on peri-implant GBR with harvested biopsies reported similar

clinical observations (Zitzmann et al., 1997, Jung et al., 2009). Histologic data

from biopsies taken 6 months after augmentation surgery with DBBM plus

collagen membrane reported newly formed bone between 23% (Zitzmann et al.,

2001b) and 30% (Jung et al., 2003) and 39% for DBBM plus non-resorbable

membrane (Friedmann et al., 2002). The mean amounts of newly formed bone in

the present study were slightly higher with 38% (RES) and 36% (N-RES) within a

similar observation period.

The outcomes of the study certainly need to be interpreted with caution. This is

mainly due to an imbalance in terms of the initial defect dimension that differed

significantly or were borderline after implant placement. Applying the more

complex mixed model, however, no effect of group interaction was demonstrated.

Moreover, the distribution of sites for the two groups was imbalanced. This short-

coming was due to the nature of the randomization process that took place

immediately after implant placement. This might have impacted the outcomes at

6 months. Interestingly, at 6 months, the differences were from a clinical point of

view negligible (even though for some outcomes measures statistically

significant). Overall, a high number of patients did not fullfill the inclusion criteria.

This was due to the need for primary bone augmentation or a lack of dehiscence

after implant placement. If a GBR was applied on the buccal side of the implant

only for contour reasons, the patient was not included in the study. Furthermore,

the production of the non-resorbable e-PTFE membranes was discontinued and

they were not available for use after the inclusion of 27 patients. This

unfortunately lead to the termination of the recruitment phase and thus did not

allow including more patients in this RCT. Still, other non-resorbable membranes

were put on the market and are available for clinical use today. Therefore, further

follow-up examinations will be performed evaluating longer term outcomes and

trying to answer the question whether or not bone regenerated using resorbable

or non-resorbable membranes around dental implants can be maintained over

time.

Conclusions

Guided bone regeneration for buccal dehiscence and fenestration-type defects

can be achieved using either membrane. This was demonstrated by a similar

vertical defect resolution and a similar horizontal thickness at 6 months in both

groups. As collagen membranes do not maintain space and thus tend to collapse,

the decrease in horizontal thickness was significantly different in favor of the

non-resorbable membrane group at 6 months. Wound dehiscences occurred at a

relatively high frequency in both groups, but were not associated with residual

vertical defect height at 6 months. Histologically, both membranes allowed for

new bone formation and contained a similar amount of bone substitute material

during 6 months.

Acknowledgements

The study was supported by the Clinic of Fixed and Removable Prosthodontics

and Dental Material Science, University of Zurich, Switzerland and by a research

grant from the Swiss Dental Association (SSO), Bern, Switzerland. In addition,

dental implant materials were provided free of charge by Dentsply (DENTSPLY

Implants, Mölndal, Sweden), whereas bone substitute materials and membranes

were provided by Geistlich Pharma AG, Wolhusen, Switzerland. The authors do

not report to have any conflict of interest to any products related to this study.

The authors are grateful to Mrs. Gisela Müller, study monitor at the Clinic for

Fixed and Removable Prosthodontics and Dental Material Science, University of

Zurich, Switzerland for her support with the data preparation for the statistical

analysis and her support during the preparation of the manuscript. The authors

would also like to address gratitude to Ms. Sonja Hitz, Clinic of Fixed and

Removable Prosthodontics and Dental Material Science, University of Zurich for

the preparation of the histologic slides. Thanks also go to Dr.Caroline

Lustenberger for her support in the statistical analysis of the collected data.

Figure Legends

Figure 1 Clinical measurements performed during implant surgery and at re-entry (6 months).

Figure 2 Treatment groups with respective membrane. Collagen membrane in resorbable group (RES) and ePTFE-membrane in non-resorbable group (N-RES).

Figure 3 Clinical picture of a site at the time of re-entry 6 months after implant placement and GBR. A trephine bur with an inner diameter of 1.8mm is used to harvest the biopsy at 3mm below the implant shoulder perpendicular to the long axis of the implant with a sink depth of 3mm.

Figure 4 Histological sample harvested with a trephine bur with the respective amounts of: 1) bone substitute material (DBBM), 2) newly formed bone and 3) soft tissue.

Table 1 Distribution of implant sites and locations in both groups.

Table 2a/b/c Bone defect dimensions and horizontal thickness in millimeters at surgery and after 6 months . Mean values, standard deviations and medians (p-value of the R-test and Wilcoxon Mann-Whitney test 2b/c).

Table 3a/b 3a Number of soft tissue dehiscences at the different time points of assessment. 3b Soft tissue condition at the 6-month re-entry (normal/red/swollen/dehiscence).

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Figure 1 Figure 2

Figure 3 Figure 4

Table 1

Table 2a

Table 2b

upper jaw (RES/N-RES) lower jaw (RES/N-RES) total

central incisors 4 (2/2) 0 4

lateral incisors 8 (1/7) 0 8

premolars 9 (9/0) 6 (4/2) 15

total 21 6 27

At Surgery At Re-entry (6m)

RES N-RES RES N-RES p-value

Defect dimensions time group

Width 3.08 (±0.18)

3.00

3.19 (±0.33)

3.00

0.73 (±0.33)

.00

0.23 (±0.23)

.00p=0.0001 p=0.36

Depth 0.92 (±0.23)

1.00

1.00 (±0.28)

.00

0.41 (±0.28)

.00

0.23 (±0.23)

.00p=0.003 p=0.75

Infrabony 0.15 (±0.15)

.00

1.00 (±0.59)

.00

0.0 (±0.0).00

0.0 (±0.0).00 p=0.02

At Surgery

RES N-RES p-value

Vertical & Horizontal Dimensions

Vertical defectmedian

4.00 (±2.07)4.00

2.36 (±2.09)2.50 p=0.0444

Horizontal thicknessmedian

3.46 (±0.52)3.00

2.82 (±0.50)3.00 p=0.0040

Table 2cAt Re-entry (6months)

RES N-RES p-value

Defect dimensions

Vertical defectmedian

0.77 (±0.85)1.00

0.21 (±0.80)0.00 p=0.0213

Horizontal thicknessmedian

1.32 (±1.38)1.00

2.68 (±1.05)3.00 p=0.0167

Loss of vertical defectmedian

3.41 (±2.33)4.00

2.14 (±2.06)2.00 p=0.1069

Loss of horizontal thicknessmedian

2.23 (±1.21)3.00

0.14 (±0.79)0.00 p=0.0001

Table 3a

Table 3b

1 week (suture removal)

4 weeks 3 months At Re-entry (6 months)

RES 4 0 0 0

N-RES 1 2 1 1

normal (e.g. healthy) red/swollen dehiscence

RES 6 2 0

N-RES 7 5 1

percentage 50.5% 25.9% 7.7%